PROJECT SUMMARY: Dr. Alex DaSilva has received his Doctor in Medical Science degree in Oral Biology with clinical training in Trigeminal Pain at Harvard University, which was followed by a post-doctoral on Migraine Neuroimaging at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital. He currently has a background in magnetic resonance imaging (MRI) methods (e.g. fMRI, DTI), and their application in pain research. The main goal of this K23 project is to provide Dr. DaSilva advanced mentoring and training on molecular neuroimaging, technology only available in selected institutions, to establish a solid independent scientific and academic career. In this project, we will integrate anatomical MRI techniques with positron emission tomography (PET) for the study of structural and molecular cortical neuroplasticity in migraine, as well as the allodynic mechanisms associated with it. The fact that many therapeutic modalities do not provide relief for these treatment-resistant patients raises the possibility that the cause for the chronicity of these debilitating disorders may lie in the brain itself, and possibly in the dysfunction of specific cortical and subcortical areas (e.g. SI, periaqueductal gray matter) and modulatory mechanisms (e.g. opioidergic mechanisms). Recent studies with PET using a selective mu-opioid receptor (MOR) radiotracer, have shown varied pattern of reduced MOR binding potential (BP) depending on the disorders investigated (e.g. fibromyalgia). These findings represent either higher occupation of MOR by endogenous ligands or loss of opioid receptors. Interestingly, our last results suggest that such molecular changes in refractory pain parallel cortical thickness and diffusional changes in areas related to pain perception and modulation in episodic migraine patients. Therefore, we will test the hypothesis that migraine is sustained by mal-adaptive changes at multiple levels of the cortex by pursuing the following Aims: 1) To investigate MOR-BP changes in chronic trigeminal pain patients compared to healthy controls; 2) To demonstrate that frequency of the headache attacks and severity of cutaneous allodynia levels in migraineurs are correlated with MORBP.3) To investigate whether MORBP levels in the PAG of migraineurs are associated with changes in the gray matter thickness changes in cortical areas associated with pain perception and modulation. RELEVANCE: As a career goal, this multidisciplinary training project will help to establish my research as an independent scientist applying PET and MRI-based neuroimaging in the study of cellular and molecular neuroplastic- ssocited mechanisms in migraine, as well as cutaneous allodynia. This project is expected to expand our knowlegde on cortical migraine pathophysiology, and possibly novel therapeutic targets in the brain.